ADAM17

Researchers from the University of Copenhagen have discovered what regulates an enzyme that is central to the growth of cancer tumors. This could be of great value to future cancer treatment.

Danish researchers from the University of Copenhagen have discovered what controls the enzyme that aids the growth of cancer tumors. These findings could be of great value to cancer treatments and has just been published in the journal, Nature Communications.

The enzyme is called ADAM17 and it aids growth in cells.

"ADAM17 is very important to the growth of cancer tumors. It functions as a molecular pair of scissors, separating molecules from the cell's surface which then increases cell growth. The problem being that in cancer cells this growth is over-activated and so the cancer tumor grows rapidly and uncontrollably," Postdoc Sarah Dombernowsky explains. She is part of Associate Professor Marie Kveiborg's research group at the Department of Biomedicine & BRICK, at Copenhagen Biocenter.

Researchers from all over the world have long been interested in finding ways to restrict ADAM17 and thus inhibit the growth of cancer tumors. Among other things, they have tried to impede the process with different drugs. However, these drugs also obstructed other important scissors, which led to patients suffering severer side effects.

This is why it is of such great importance that Sarah Dombernowsky and her colleagues have now located a mechanism that controls ADAM17.

The cancer tumor cannot grow

"We have discovered that the protein PACS-2 plays a big part in the transportation of ADAM17 in cells. ADAM17 moves in and out of the cell, but it has to remain on the surface to be able to cut off molecules and thus further growth. We have showed that without the PACS-2, ADAM17 returns less regularly to the surface; it's broken down instead," Sarah Dombernowsky elaborates.

Thus ADAM17 is rendered incapable of helping the cancer tumor grow and it provides us with fundamental knowledge, which may be used to improve future cancer treatments.

"There have been attempts at developing a pill to inhibit ADAM17, only the patients became ill due to side effects, because other, similar enzymes were also affected. But if you inhibit PACS-2, you can, in principle, obstruct only ADAM17, which would enable us to inhibit the growth of the cancer tumor," Sarah Dombernowsky states.

Marie Kveiborg's group is currently conducting animal experiments to learn more about the effect of ADAM17-inhibition.

"We're currently experimenting on mice to see if the cancer growth slows down, and it is our distinct expectation that it will. In the long-term, we would like to develop something that through PACS-2 allows us to fine-tune ADAM17, which could then eventually become part of a more targeted cancer treatment," Sarah Dombernowsky concludes.

(Jan. 18, 2008) — Scientists at Jefferson's Kimmel Cancer Center in Philadelphia have made an extraordinary advance in the understanding of the function of a gene previously shown to be part of an 11-gene "signature" that can predict which tumors will be aggressive and likely to spread. The gene, USP22, encodes an enzyme that appears to be crucial for controlling large scale changes in gene expression, one of the hallmarks of cancer cells.

As a result, USP22 immediately becomes a potential target for new anti-cancer drugs, says Steven McMahon, Ph.D., associate professor of Cancer Biology at Jefferson Medical College of Thomas Jefferson University, who led the work. And it solves a bit of a biological mystery.

Researchers knew that the gene USP22 was part of a group of 11 genes that are overexpressed in a variety of cancers and that overexpression of USP22 predicts which tumors can go on to spread elsewhere in the body. This group of genes is collectively called the "cancer stem cell signature."

"Such cancers that have those properties -- going on to be metastatic and resistant to therapy -- are referred to as having cancer stem cell-like features," Dr. McMahon explains. "The genes in the signature are in a family of genes implicated as cancer stem cell markers. Many of them code for critical components of signaling pathways that are altered in cancer, making proteins that play roles in tumor growth." But unlike the other genes in the stem cell signature, the exact function of USP22 was not known.

L'exact fonction de USP22 n'était pas connue.

Reporting January 18, 2008 in the journal Molecular Cell, Dr. McMahon and his co- workers have shown that not only is USP22 overexpressed in cancer cells, its enzymatic activity is necessary for some of the global changes in gene expression patterns that occur in these cells.

In one example, they looked at the relationship between MYC and USP22. MYC, which is among the most commonly overexpressed genes in cancer, encodes a protein that controls the expression of thousands of other genes. The scientists showed that USP22 is a critical partner of MYC and that by depleting cells of USP22, they could prevent MYC from working properly, stopping it from inducing the invasive growth of cancer cells.

"We've shown that the MYC pathway is among the transcriptional programs that require USP22," Dr. McMahon says. "Identifying USP22 as a global transcription regulator helps explain why it is part of this aggressive stem cell signature."

Dr. McMahon and his group determined how USP22 works at the biochemical level and found that it is part of a large complex of proteins called human SAGA. According to Dr. McMahon, these proteins are responsible for turning on genes, helping them get expressed more efficiently. This suggests that the genes that are turned on by the USP22 complex are important for altering cancerous cells in such ways that they become more aggressive and metastatic.

"Discovering the identity of the 11-gene signature that predicts aggressive, therapy- resistant tumors a few years ago was certainly a critical advance in terms of the ability to diagnose and stratify patients," Dr. McMahon says. "Since USP22 is an enzyme, the type of protein that is easiest to target with drugs, our new findings may help extend these earlier discoveries to the point where therapeutics can be developed. There are already drugs being used in cancer patients that attack other enzymes in this pathway, and there are companies interested in extending this to find USP22 inhibitors."